Background. Libman-Sacks endocarditis with vegetations is the most serious heart disease of systemic lupus erythematosus (SLE). Neuropsychiatric SLE (NPSLE) which includes stroke and transient ischemic .attacks is associated with increased morbidity and mortality. Our published data demonstrate that: 1) Libman-Sacks orthrombotic vegetations are detected by transesophageal echocardiography (TEE) in 35% of SLE patients; and 2) NPSLE affects 60% of patients. Our preliminary data in 37 patients with SLE demonstrate that: 1) 27 patients (73%) had NPSLE; 2) 14 (38%) had cerebral infarcts on MRI; 3) 22 (59%) had valve vegetations detected by TEE, mostly on the mitral valve (82%); 4) cerebral infarcts were more common in patients with than without NPSLE (48% vs. 10%, p = 0.056); 5) mitral valve vegetations were more common in patients with than without NPSLE (63% vs. 10%, p = 0.008); and of most importance, 6) mitral valve vegetations were the strongest independent predictor of NPSLE (odds ratio 15.3, 95% Cl 1.7 - 139, p = 0.005). Thus, thromboembolism from valve vegetations is likely a major cause of NPSLE. Hypothesis: Valve vegetations generate macro- and microemboli that occlude the medium and small cerebral vessels resulting in altered perfusion, ischemic brain injury, and NPSLE. Experimental. This is a prospective controlled cross-sectional and longitudinal study to determine the role of valve vegetations as a major cause of NPSLE. Patients will be recruited from our SLE cohort of 437 subjects. During the cross-sectional phase, 31 subjects with new or recurrent NPSLE, 31 subjects without NPSLE, and 20 age and sex matched controls will undergo: 1) TEE to detect valve vegetations; 2) transcranial Doppler for detection of microemboli; 3) carotid duplex to assess intimal-media thickness and carotid plaques; 4) assessment of SLE and NPSLE activity and severity; 5) neuropsychiatric testing; 6) assessment of coagulation and platelet activation by measurement of antiphospholipid antibodies, prothrombin fragments 1.2, thrombin-antithrombin III complexes, and platelet aggregation; and 7) cranial MRI, diffusion weighted imaging and perfusion weighted imaging for assessment of brain injury and cerebral perfusion. During the longitudinal phase of 48 months, 1) subjects with NPSLE in the remission phase; and 2) subjects with new or recurrent NPSLE will undergo repeat clinical, cardiovascular and cerebral imaging evaluations to further determine a temporal association of vegetations with microemboli, brain injury, and NPSLE. Significance. This integrated cardiovascular-brain imaging approach provides a powerful experimental design that will demonstrate a causal relationship of valve vegetations to the generation of microemboli, ischemic brain injury, arid thus, NPSLE. These findings will establish: 1) cardioembolism as a major cause of NPSLE; 2) new strategies for the diagnosis of valve disease and NPSLE; and 3) the scientific basis for a future trial of selective antithrombotic, anticoagulant, or anti-inflammatory therapy to prevent the progression and recurrence of valve vegetations and NPSLE. [unreadable] [unreadable]